Phase 1b Study of EZH1/2 Inhibitor Valemetostat in Combination With Trastuzumab Deruxtecan in Subjects With HER2 Low/Ultra-low/Null Metastatic Breast Cancer

To find a recommended dose of valemetostat that can be given in combination with trastuzumab deruxtecan to patients with low/ultra-low HER2-expressing metastatic breast cancer.

Inclusion Criteria: 1. ≥18 years of age or the minimum legal adult age (whichever is greater) at the time the informed consent form (ICF) is signed. 2. Pathologically confirmed HER2 low/ultra-low/null breast cancer. HER2 low is defined as IHC 2+/ISH- or IHC 1+/(ISH- or undefined), HER2 ultra-low is defined as IHC 0 with detectable faint/barely perceptible incomplete staining in ≤10% tumor cells and HER2 null is defined as IHC 0 without any observed tumor cell staining, regardless of hormone receptor expression status, and as determined by the Ventana 4B5 IHC assay The accrual numbers of HER2 ultra-low/null and HER2 low should be approximately 1:1 in the dose-escalation and dose-expansion cohort (i.e., 6 subjects for HER2 ultra-low/null and 6 subjects for HER2 low in dose-escalation cohort, 10 subjects for HER2 ultra-low/null and 10 subjects for HER2 low in dose-expansion cohort). Initial subject inclusion may be based on previously obtained HER2 testing results, however final HER2 status determination (HER2 low, ultra-low, or null) will be based on centralized pathologist (re)evaluation of HER2 IHC staining using the Ventana 4B5 assay at MDA Department of Pathology laboratory. If HER2 eligibility assessment and subject inclusion are based on results from a previous HER2 IHC test performed with an IHC assay different from the Ventana 4B5 assay, or if the IHC slides from the initial test are not available for re-evaluation, adequate material for HER2 testing using the Ventana 4B5 assay must be provided to MDA Department of Pathology laboratory. 3. MBC or locally progressive breast cancer that is not a surgical candidate. 4. Has progressed on and would no longer benefit from endocrine therapy in hormone receptor-positive subjects. 5. Has been treated with at least 1 prior line of chemotherapy in the metastatic or locally progressive setting. 6. Has adequate treatment washout period by the time of enrollment, defined as: Treatment Washout Period Major surgery ≥ 4 weeks Radiation therapy including palliative stereotactic radiation to chest ≥ 4 weeks Palliative stereotactic radiation therapy to other anatomic areas ≥ 2 weeks Anti-cancer chemotherapy (Immunotherapy \[non-antibody based therapy\]), retinoid therapy, hormonal therapy * 3 weeks Targeted agents and small molecules ≥ 2 weeks or 5 half-lives, whichever is longer Nitrosoureas or mitomycin C ≥ 6 weeks Antibody-based anti-cancer therapy ≥ 4 weeks Chloroquine/Hydroxychloroquine \>14 days 7. Has at least one measurable lesion per RECIST (except for up to the first 5 subjects who enroll in dose escalation part where the measurable lesions meeting RECIST definition are not mandatory). 8. Is willing to provide fresh tumor tissue via tumor biopsy only if the participant has a disease that can be safely accessed through a CT-guided/US-guided or percutaneous biopsy for multiple core biopsies judged by the investigator. If the participant doesn't have a disease that can be safely accessed, they are still eligible. 9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1. 10. Negative serum pregnancy test within 72 hours of receiving the first dose of the study medication for women of childbearing potential as per institutional guidelines. Post-menopausal women (defined as having no menses for at least 1 year) and surgically sterilized women are not required to undergo pregnancy tests. 11. Subjects of childbearing potential must be willing to use effective birth control methods or be surgically sterile or abstain from heterosexual activity for the course of the study through at least 4 months after the last dose of the study drug (for males) and 7 months after last dose of study drug (for females). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for at least 1 year. 12. Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 3 months after the final study drug administration. 13. Male subjects must not freeze or donate sperm starting at Screening and throughout the study period, and for at least 3 months after the final study drug administration. 14. The patient must have adequate organ function as determined by the following laboratory values: 1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × the upper limit of normal (ULN). For those with liver metastasis, ALT and AST ≤5.0 × ULN. 2. Total bilirubin ≤1.5 × ULN, except for subjects with Gilbert's syndrome (e.g., a gene mutation in UGT1A1), who can have total bilirubin \